Physiochemical Properties Flashcards
What must an “ideal” oral drug be?
Dissolve
Survive in 1.5-8.0 pH range
Survive intestinal bacteria
Cross membranes
Survive liver metabolism
Avoid active transport to bile
Avoid excretion by kidneys
Partition into target organ
Avoid partition to undesired places
What is a physiochemical property?
A parameter that can be derived from physical + chemical characteristics of a molecule
What are the physiochemical properties?
Solubility
Stability
Solid-state properties
Partition coefficient
Ionisation constant
What is Lipinski’s rule of 5?
No more than 5 H bonds
No more than 10 H bond donors
Mr <500
LogP <5
What is lipophilicity?
Ability of chemical compound to dissolve in fats, oils, lipids + non-polar solvents
What does lipophilicity determine?
ADMET
What does it mean if logP is high?
High lipophilicity
How do you determine logP using shake flask method?
Look at distribution between octanol + H2O
Analyse drug conc by UV
How do you determine logP using chromatography?
Microtiter plate format
Compound detection by MS
Retention time linked to partition coefficient
Limited by compound properties - eg. purity
What is clogP?
Calculated logP
What happens to binding as logP increases?
Increases
What happens to aqueous solubility as logP increases?
Decreases
What happens to absorption through membrane as logP increases?
Increases
What is the substituent hydrophobicity constant?
Measure of substituent’s hydrophobicity relative to H
What does positive values of the substituent hydrophobicity constant indicate?
More hydrophobic (lipophilic) than H
What does negative values of the substituent hydrophobicity constant indicate?
Less hydrophobic than H
How is it possible to calculate logP (clogP) from substituent hydrophobicity constant?
LogP + value + value
What do you use when comparing neutral molecules?
logP
What do you use when comparing mixed neutral + charged molecules?
logP
What do you use when comparing all charged molecules?
logD
What happens to logD in acidic drugs when pKa increases?
More ionised = logD decreases
What happens to logD in basic drugs when pKa increases?
LogD increases
Describe fluorine
Small atom
High electronegativity
What does covalently bound fluorine do?
Occupy vol smaller than methyl, amino or hydroxyl groups
BUT larger than H atom
When you add F to an acid what happens?
CH3COOH —-> CH2FCOOH
pKa decreases = increased acidity
What happens to lipophilicity if you substitute H for F?
Increases lipophilicity slightly
What happens to logD if you substitute H for F?
Decreases
What are the ways of investigating molecular size?
e- density
Molecular weight
Polar surface area
Van der Waals
Molar refractivity
What is the Hammett substituent constant?
A measure of electron-withdrawing or electron-donating influence of substituents
How can the Hammett substituent constant be measured?
Experimentally or tabulated
What will electron-withdrawing groups have?
Hammett substituent constant
Positive value
What will electron-donating groups have?
Hammett substituent constant
Negative value
What happens in electron-withdrawing groups?
Hammett substituent constant
Charge stabilised by X
Eqm shifts right
Kx > KH
What happens in electron-donating groups?
Hammett substituent constant
Charge destabilised
Eqm shifts left
Kx < KH
What are the 2 types of substitution?
Meta
Para
What is meta due to?
Inductive effect
What is para due to?
Inductive + resonance effects
Describe aliphatic electronic effects
Purely inductive effects
Hydrolysis rates measured under basic + acidic conditions
Defined by σI
If X is electron donating what will happen to hydrolysis rate of aliphatic electronic effects?
Decreases
If X is electron withdrawing what will happen to hydrolysis rate of aliphatic electronic effects?
Increases
What is molecular polar SA?
Surface sum of all polar atoms present in the molecule
Usually N, O + their attached H
How is molecular polar SA calculated?
From surface/space filling models
How do rotatable bonds effect?
Increased flexibility reduces oral bioavailability = <10
How do H bond donors + acceptors effect?
Polarity reduces permeability
Lipinski’s rule
How do aromatic rings effect?
Effect solubility
How does pKa effect?
Drug needs to be ionised
pKa needs to be relevant to logD + target binding site
What does it mean if there is a high logS value?
Good solubility
